Although HIV-infected individuals are achieving greater life-expectancy, the population is experiencing a growing burden of chronic kidney disease (CKD). CKD develops at much younger ages in HIV-infected than uninfected persons, and is associated with substantially higher risks for cardiovascular disease, heart failure, and mortality. These already elevated risks of kidney disease and its complications are amplified by the widespread use of tenofovir disoproxil fumarate (TDF), which is currently used by approximately two-thirds of HIV-infected persons in the US, and is independently associated with a doubling in risk for CKD compared with alternative regimens. Both in the United States and worldwide, TDF-containing therapies are first-line for long- term therapy of HIV. Despite the importance of CKD as a complication of HIV and the kidney risks of TDF, current practices for kidney disease screening and diagnosis remain essentially unchanged since the beginning of the HIV epidemic. As a consequence we lack effective strategies to detect early kidney damage from TDF, to distinguish kidney damage caused by TDF from other CKD risk factors, or to quantify risk accurately for the onset and progression of CKD. During our initial funding period, our research team demonstrated the remarkable potential of several urine biomarkers of kidney injury to detect and quantify subclinical kidney damage, to characterize the influence of specific risk factors, and to forecast subsequent declines in kidney function. This novel approach could dramatically transform the process of screening, diagnosing and treating kidney disease in HIV-infected persons. In this renewal R01 application, we have the practice-changing objectives of developing and validating two distinct multiplex urine biomarker panels: the Tenofovir Injury Panel and the CKD Risk Panel. We will evaluate 15 candidate urine biomarkers that quantify damage and dysfunction within distinct compartments of the kidney, and we will select the optimal combinations to maximize: 1) detection of kidney abnormalities at their earliest stages; 2) discernment of TDF specific damage; and 3) prognosis of kidney disease risk. To accomplish both development and validation stages for our biomarker combinations, we will conduct our research across five multi-center studies that have available biological specimens and that have welcomed our collaboration on this proposal: the Preexposure Prophylaxis Initiative trial (iPrEx), the Women's Interagency HIV Study (WIHS), the Multicenter AIDS Cohort Study (MACS), the Biopsy Examination of AIDS Nephropathy (BEANS), and the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN). Our multi-disciplinary team of expert investigators will ensure the success of this project. At its conclusion we will design a randomized clinical trial to determine whether our advanced methods to detect, diagnose and stage kidney disease can improve the safety of HIV therapy without sacrificing its clinical effectiveness.